2.1. Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) is a human retrovirus believed to be the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC). The HIV virion or virus particle is a sphere that is roughly 1000 angstrom units across. The particle is covered by a lipid bilayer membrane derived from the outer membrane of the infected host cell. Studding the viral membrane is an envelope glycoprotein which is synthesized as a precursor of 160 kd and subsequently processed into two glycoproteins: gp41 which spans the lipid bilayer, and gp120 which extends beyond the lipid bilayer. The envelope covers a core made up of proteins designated p24 and p18. The viral RNA is carried in the core, along with several copies of the enzyme, reverse transcriptase, which catalyzes the assembly of viral DNA.
The HIV genome contains three genes that encode the components of retrovirus particles: env (which codes for the envelope proteins), gag (which codes for the core proteins), and pol (which codes for reverse transcriptase). These three genes are flanked by stretches of nucleotides called long terminal repeats (LTRs). The LTRs include sequences that have a role in controlling the expression of viral genes. However, unlike other retroviruses, the genome of HIV includes at least five additional genes, three of which have known regulatory functions, and the expression of which is thought to have an impact on the pathogenic mechanisms exerted by the virus. The tat gene encodes a protein that functions as a potent trans-activator of HIV gene expression, and, therefore, plays an important role in the amplification of virus replication. The rev, or trs/art gene can upregulate HIV synthesis by a transacting antirepression mechanism; rev enables the integrated HIV virus to selectively produce either regulatory proteins or virion components. In contrast, the nef, or 3'-orf, gene appears to down-regulate virus expression by producing a cytoplasmic protein which, presumably via a second messenger, inhibits transcription of the HIV genome. The vif, or sor gene is not essential for virion formation, but is critical to the efficient generation of infectious virions and influences virus transmission in vitro. The pr, or R gene encodes an immunogenic protein of unknown function.
An important basis for the immunopathogenesis of HIV infection is believed to be the depletion of the helper/inducer subset of T lymphocytes, which express the CD4 antigen, resulting in profound immunosuppression. Viral killing of these immune cells is thought to be a major factor contributing to the crippling effect HIV has on the immune system. The envelope glycoprotein appears to play an important role in the entry of HIV into CD4 positive host cells. The gp120 portion has been shown to bind directly to the cellular CD4 receptor molecule, thereby producing HIV's tropism for host cells that express the CD4 receptor, e.g., T helper cells (T4 cells), macrophages, etc.
After HIV binds to the CD4 molecule, the virus is internalized and uncoated. Once internalized, the genomic RNA is transcribed into DNA by the enzyme reverse transcriptase. The proviral DNA is then integrated into the host chromosomal DNA and the infection may assume a "dormant" or latent phase. However, once activation occurs, the proviral DNA is transcribed. Translation and post translational processing results in virus assembly and budding of mature virions from the cell surface.
When active replication of virus occurs, the host CD4+ cell is usually killed, but some cells may persistently produce virus and are not killed. However, the precise mechanism by which HIV exerts its cytopathic effect is unknown, and in fact CD4 cell killing has been observed with exposure to inactivated virus. A number of mechanisms for the immunopathogenesis and cytopathic effect of HIV infection have been proposed: the accumulation of large amounts of unintegrated viral DNA in the infected cells; massive increase in permeability of the cell membrane when large amounts of virus bud off the cell surface; speculations that HIV may induce terminal differentiation of infected T4 cells, leading to a shortened life span. There is growing evidence that both the CD4 molecule and the virus envelope play a role in cytopathic effect in HIV infected cells by somehow promoting cell fusion. A prominent feature in the cytopathology of HIV infection is the formation of multinucleated syncytia formed by the fusion of as many as 500 cells which appear to be induced by the gp120/gp41 envelope proteins. In contrast, HIV-infected macrophages may continue to produce HIV without cytopathic effects for long periods of time; it is believed that the macrophage is a major reservoir for HIV and may be responsible for transporting virus into the central nervous system (Gartner et al., 1986, Science 233:215-219).
To date, there is no cure for AIDS. Vaccine trials are currently underway in an attempt to control the spread of the virus among the population. However, efforts at controlling the course of disease within an infected patient have been directed mainly towards the use of antiviral agents.